The objective of Project 3 is to characterize the role played by a highly novel form of chromatin regulation? substitution of histone variants?in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in mediating depression- and antidepressant-like responses in animal models. Exciting new research, much of it from our laboratory, has demonstrated that, in addition to post-translational modifications of histones, eukaryotic cells, including mature neurons, further generate chromatin structural variation through the introduction of variant histone proteins into existing nucleosomes. We focus here on histone H3.3, which we have shown is enriched in mature neurons and dynamically regulated by neural activity. Its deposition depends in part on specific histone modifications, including those examined in Projects 1 and 2. Moreover, our data indicate that H3.3 is incorporated into nucleosomes at genes undergoing activation or repression in response to neuronal activity, neurotransmitters, and neurotrophic factors. Recently, we demonstrated that neural activation in vivo by use of optogenetic tools, or exposure to chronic stress, also regulates H3.3 expression in PFC and NAc. We have seen altered levels of H3.3 in the PFC and NAc of depressed humans as well. These highly novel findings set the stage for our proposed investigations. We will characterize regulation of H3.3 expression in PFC and NAc in both adult and early life stress models as well as map genome-wide stress-induced changes in the deposition of H3.3 in these models. Additionally, we will use biochemical methods, with which our laboratory has extensive expertise, to identify novel interacting proteins that associate with H3.3 in brain under basal and stress conditions. Finally, we will directly characterize the functional importance of H3.3 deposition in depression models by utilizing unique gain- and loss-of-function tools established by our group to investigate the effect of manipulating H3.3 within PFC or NAc neurons on responses to stress and antidepressant treatments at the behavioral, chromatin, and gene expression levels. Parallel studies of H3.3 will be carried out on PFC and NAc of depressed humans in conjunction with Project 4. These studies provide a template for the analysis of the roles played by other key histone variants in depression.

Public Health Relevance

Depression has a lifetime risk of ~15% for the U.S. general population, yet available antidepressant therapies are based on serendipitous discoveries over 6 decades ago, and fully treat <50% of all affected individuals. An improved understanding of the molecular basis of depression will lead to improved treatments and diagnostic tests-a high priority for the National Institutes of Health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH096890-03
Application #
8672686
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$289,752
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Labonté, Benoit; Engmann, Olivia; Purushothaman, Immanuel et al. (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102-1111
Zhao, Jian-Yuan; Liang, Lingli; Gu, Xiyao et al. (2017) DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 8:14712
Nätt, Daniel; Barchiesi, Riccardo; Murad, Josef et al. (2017) Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain. Sci Rep 7:11082
Loh, Yong-Hwee Eddie; Feng, Jian; Nestler, Eric et al. (2017) Bioinformatic Analysis for Profiling Drug-induced Chromatin Modification Landscapes in Mouse Brain Using ChlP-seq Data. Bio Protoc 7:
Peña, Catherine J; Kronman, Hope G; Walker, Deena M et al. (2017) Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356:1185-1188
Lopez, Juan Pablo; Fiori, Laura M; Cruceanu, Cristiana et al. (2017) MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun 8:15497
Jiang, C; Lin, W-J; Sadahiro, M et al. (2017) VGF function in depression and antidepressant efficacy. Mol Psychiatry :
Ménard, Caroline; Pfau, Madeline L; Hodes, Georgia E et al. (2017) Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience. Neuropsychopharmacology 42:62-80
Brancato, Anna; Bregman, Dana; Ahn, H Francisica et al. (2017) Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Neuroscience 350:180-189
Feng, Jian; Pena, Catherine J; Purushothaman, Immanuel et al. (2017) Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors. Neuropsychopharmacology 42:1657-1669

Showing the most recent 10 out of 192 publications